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Preventive effects of several chemicals against lethality of recombinant human tumor necrosis factor
N Satomi1, A Sakurai, R Haranaka
1Department of Internal Medicine, University of Tokyo, Japan.
Abstract:
Toxicity has been observed in mice receiving recombinant human tumor necrosis factor (rhTNF). In the present experiments, several chemicals were used to determine whether they could prevent the lethality of rhTNF without impairing its antitumor activity. Injection of phospholipase A2, cyclooxygenase, and lipoxygenase inhibitors at the same time as rhTNF administration could prevent the lethality of rhTNF, but the antitumor activity was also reduced. Urinastatin and reduced glutathione could prevent the lethality while reducing the activity. In contrast, by pretreatment with O2 scavengers, the lethality of rhTNF was markedly reduced without impairment of the antitumor activity of rhTNF. Antihistamines exerted no influence on the lethality of rhTNF. Histopathologic examinations have demonstrated that the capillaries of the tumor tissue show aggregation of platelets and formation of fibrin adherent to the vascular surface after TNF administration. Heparin or protamine revealed no effects against the lethality of rhTNF. These results strongly suggest that the arachidonic cascade is deeply related to the antitumor activity of TNF and its side effects. Pretreatment with O2 scavengers, especially bismuth subnitrate, could prevent the lethality of rhTNF without impairing its antitumor activity.
Insights
Oxygen scavengers, like bismuth subnitrate, effectively reduce the toxicity of recombinant human tumor necrosis factor (rhTNF) in mice. This pretreatment preserves rhTNF
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Recombinant human tumor necrosis factor (rhTNF) exhibits antitumor activity but also causes significant toxicity in preclinical models.
- Understanding the mechanisms underlying rhTNF-induced lethality is crucial for optimizing its therapeutic application.
- The role of inflammatory mediators and vascular effects in rhTNF toxicity requires further investigation.
Purpose of the Study:
- To identify chemical agents that can mitigate rhTNF-induced lethality without compromising its antitumor efficacy.
- To elucidate the biochemical pathways involved in rhTNF toxicity and antitumor activity.
- To evaluate the potential of oxygen scavengers as protective agents against rhTNF side effects.
Main Methods:
- Mice were treated with rhTNF and various chemical agents, including enzyme inhibitors, antioxidants, and anticoagulants.
- Lethality and antitumor activity were assessed following different pretreatment strategies.
- Histopathological examination of tumor vasculature was performed to analyze microvascular changes.
Main Results:
- Inhibitors of phospholipase A2, cyclooxygenase, and lipoxygenase, as well as urinastatin and reduced glutathione, reduced rhTNF lethality but also impaired its antitumor activity.
- Pretreatment with oxygen (O2) scavengers markedly reduced rhTNF-induced lethality without affecting antitumor activity.
- Histopathology revealed platelet aggregation and fibrin formation in tumor capillaries post-rhTNF administration, suggesting vascular involvement.
Conclusions:
- The arachidonic acid cascade is implicated in both the antitumor effects and toxicities of rhTNF.
- Oxygen scavengers, particularly bismuth subnitrate, represent a promising strategy to mitigate rhTNF lethality while preserving therapeutic efficacy.
- Targeting O2-mediated pathways may enhance the clinical safety profile of rhTNF-based therapies.